Over the past few years, we have synthesized over 500 3-phenyltropane analogs that have been evaluated for binding at the dopamine, serotine, and norepinephrine transporters (DAT, 5-HTT, and NET, respectively). These studies identified 47 analogs that showed high affinity at the DAT with low affinity at the 5-HTT and NET. Preliminary animal studies have shown that some of the DAT-selective 3-phenyltropanes enter the brain much more slowly than cocaine, have half-lives in the brain much longer than cocaine, are recognized by animals as cocaine in drug administration studies, and reduce the intake of cocaine by animals trained to self- administer cocaine. Thus, these DAT-selective 3-phenyltropanes possess several properties that are believed to be required for a medication. The goal of this SPIRCAP is to develop a safe and effective medication for treating patients addicted to cocaine. Under the direction of Dr. F. Ivy Carroll of the Research Triangle Institute, This project will provide the synthesis of the 3-phenyltropane analogs needed for study in other SPIRCAP projects of this application. The compounds selected for synthesis have high affinity for the DAT and much lower affinity for the 5-HTT and NET (i.e., they are DAT-selective). The project will involve the synthesis of 500 mg each of the DAT-selective 3-phenyltropanes needed in the gross observation, locomoter activity, and drug discrimination studies proposed in Project 2. It is expected that the studies in Project 2 will lead to the identification of six analogs which will undergo self-administration studies in rats in Project 3. Four of these compounds will be prepared in 50-m quantities for self-administration studies in monkeys in Project 4, preliminary toxicology studies (to be provided by NIDA), general receptor specificity (Novascreen), and general pharmacology (MDS Panlabs), and additional rat and monkey pre-clinical evaluation (projects 3 and 4). This information will be used to select the 3-phenyltropane for Phase 1 clinical evaluation. NIDA-MDD will arrange the synthesis of the cGMP material of this compound. This project also encompasses the synthesis the starting compound for the cGMP material, the [2H]- and [14C]-labeled analogs required for the ADME studies, and the formulation development and manufacture of the finished dosage form (under a contract with OREAD) as well as the stability studies of the cGMP material before and after formulation.